Resistance to RAF- and MEK-targeted therapy is a major clinical challenge1–4. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance5–14. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.

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Background: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). Patients and methods: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts AeF). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). Results: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n ¼ 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade !3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade !3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%e71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre-and on-treatment sTILs were significantly associated with higher pCR rates (P ¼ 0.0127, 0.0059, and 0.0085, respectively). Conclusion: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. Trial registration: ClinicalTrials.gov identifier: NCT02622074.

9520 Background: Signaling via LAG-3 and other T-cell inhibitory receptors (eg, PD-1) can lead to T-cell dysfunction and tumor immune escape. Simultaneous blockade of LAG-3 + PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study, BMS-986016 (IgG4 mAb targeting LAG-3) ± nivo (IgG4 mAb targeting PD-1) demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity (NCT01968109; Lipson E, et al. J Immunother Cancer. 2016;4[s1]:173 [P232]). Here we describe preliminary efficacy of BMS-986016 + nivo in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, along with updated safety from all dose expansion pts. Methods: Pts with MEL must have had prior anti–PD-1/PD-L1 (± anti–CTLA-4 or BRAF/MEK inhibitors) and progressive disease (PD). Pts received BMS-986016 80 mg + nivo 240 mg IV Q2W. Primary objectives were safety and objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + uCR + PR + uPR + stable disease [SD] > 12 wk), and duration of response (RECIST v1.1). Results: At data cutoff, 43 pts with MEL had been treated with BMS-986016 + nivo following PD on/after prior anti–PD-1/PD-L1 with known prior best responses of 1 CR, 9 PR, 12 SD, and 16 PD. Of the 43 pts, 30 (70%) also had prior anti–CTLA-4, 20 (47%) had ≥ 3 prior therapies, and 15 (35%) had BRAFmutations .In the 31 efficacy-evaluable pts to date, ORR was 16% (confirmed/unconfirmed) and DCR was 45% with benefit observed even in some pts refractory to prior anti–PD-1. Evaluations are ongoing for most pts, with median treatment duration of 10 wk for all 43 pts. Immunopathologic (eg, PD-1/PD-L1 and LAG-3 expression) and clinical characteristics of responders vs nonresponders will be presented. Any grade and grade 3/4 treatment-related AEs occurred in 46% and 9%, respectively, across all dose expansion pts (n = 129). Conclusion: Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. Clinical trial information: NCT01968109.

Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway 1 . Several Smoothened inhibitors (Smoi) are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma 2 . Vismodegib, a Smoi, leads to BCC shrinkage in the majority of the BCC patients 3 , but the mechanism by which it mediates BCC regression is currently unknown. Here, we used two different genetically engineered mouse models 4 to investigate the mechanisms by which Smoi mediates tumor regression. We found that vismodegib mediates BCCs regression by inhibiting hair follicle-like fate and promoting the differentiation of tumour cells (TCs). However, a small population of TCs persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans 5 . In both mouse and human BCC, this persisting slow-cycling tumour population expresses Lgr5 and is characterised by active Wnt signalling. Lgr5 lineage ablation or Wnt signalling inhibition together with vismodegib leads to BCC eradication. Our study reveals that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors constitutes a clinically relevant strategy to overcome tumour relapse in BCC.